J I MMY O. BARTLETT, 0.0. MICHAEL O. WESSON, 0.0. J ANET SWIATOCHA, 0.0. THOMAS WOOLLEY, P b.O.

ABSTRACT Background: The topical admin istration of eyedrops is often an unpleasant procedure in the pediatric population. We sought to learn whether a combination mydriatic'cycloplegic so­lution would be an effective cycloplegic if deliv­ered as a spray. Methods: We conducted a prospective, exam· iner-masked, parallel·group study and random· ized 38 subjects (age range 6 months to 12 years, mean=7.3 years) into four groups such that the same combination mydriatic-cycloplegic solu­tion was administered under the following con­ditions: 1) eyedrops to eyes that were open; 2) eyedrops to eyes that were closed; 3) spray to eyes that were open; 4) spray to eyes that were closed. Both eyes of each subject received the solutions administered under One of the four conditions. Residual accommodation was meas­ured using dynamic retinoscopy and the subjec­tive push-up method, where applicable, at times 0, 10,20, 30, 45, and 60 mins following admin· istration of the medications. Results: Repeated measures analysis of covar­iance revealed no statistically significant differ­ence (p>O.05) in cycloplegic efficacy among the four methods of drug delivery. Conclusions: The results of this study suggest that administering cycloplegics by spray to the closed eye is as efficacious as instilling eyedrops to the open eye. Use of a cycloplegic spray can have important clinical advantages compared to conventional cycloplegic eye<irops administered to children.

KEY WORDS: ophthalmic spray, mydriatic, cy­cloplegic, drug administration, pupils, accom­modation

Bartlett JO, Wesson MD, Swiatocha J, Woolley T. Efficacy of a pediatric cycloplegic adminiatered as a spray. J Am Optom Assoc 1993; 64:617-21.

Efficacy of a pediatric cycloplegic administered as a spray

T opical administration of mydriatic and cycloplegic eyedrops is often an unpleasant procedure associated with significant side ef­fects such as burning, st inging, and tearing. This is especially true in the pediatric population, in which avoidance of drug administra­tion is common. A more acceptable alternative to eyedtop applica­tion may be use of the same mydriatic and cycloplegic agents delivered to the eye as a spray. Sharp and Hanna l previously reported the efficacy of a mydriatic spray, but this study was not specifically directed at the pediatric population and had several methodological problems. We have shown,2 however, that mydriatic combinations, when delivered as a spray, can be as efficacious and safe as the same mydriatic solutions administered in conventional eyedrop form.

In the pediatric age group, manifest subjective refractive tech· niques are often difficult at best. The clinician frequently relies on objective refractive procedures such as cycloplegic retinoscopy. We wished to learn whether administration of a mydriatic-cycloplegic combination spray to the pediatric patient would have the same cycloplegic efficacy as a solution administered in conventional eyedrop fo rm. Since drug administration can be greatly enhanced if cycloplegics could be applied to the closed eyes of the pediatric patient, we further investigated if the cycloplegic spray would have the same efficacy as cycloplegic eyedrops applied to either open or closed eyes.

Methods

Potential subjects were screened for participation in the study according to the criteria listed in Table 1. After screening, 38 subjects were entered into the study, 20 (53 percent) of whom were male, and 23 (61 percent) were Caucasian. Subjects ranged in age from 6 months to 12 years (mean=7.3 years). Of the 38 subjects, 9 (24 percent) had blue irides, 26 (68 percent) brown irides, and 3 (8 percent) were classified as "other."

We conducted an examiner· masked (by third-party drug ad­ministration), parallel·group study approved by the Institutional Review Board of the University of Alabama at Birmingham. The parent or guardian of each subject signed an appropriate informed consent in which the nature and possible consequences of t he study were explained. The cycloplegic solution was prepared by mixing 3.75 ml cyclopento\ate 2.0%, 3.75 ml phenylephrine 10%, and 7.5 ml t ropicamide 1.0%, yielding a final 15 ml solution consisting of cyclopentolate 0.5%, phenylephrine 2.5%, and tropicamide 0.5%.3 T his solution was introduced into the original tropicamide droptai­ner and labeled "combination drops." Before introducing the com­bination drops into the droptainer, the container was rinsed several times using sterile saline and then air dried. A second bolus of the same solution was prepared and added to a commercially available pump atomizer (Ouray-Pretty Neat, Kearny, N.J.) that had been asepticized with 3% hydrogen peroxide. When activated, the at­omizer delivered a spray volume of approximately 30 ~1.

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Table I: EIiSibility criteria

• Male of female • 0-12 years of age • Any refractive error • Normotensive • Open anterior chamber angles • Taking no ocular or systemic medications

known to affect pupil size or accommodation • No history of ocular disease or intraocular

surgery

The subjects were randomized into one of four groups to receive: 1) one drop of combination solution to both open eyes; 2) one drop of combination solution to both closed eyes; 3) one "pump" of spray to both open eyes; and 4) one "pump" of spray to both closed eyes. Each subject received the cycloplegic under only one condition. Under both "drop" conditions, the sub­ject's head was inclined backward, and the combination solution was applied either to the interpalpebral fissure under "closed-eye" conditions or to the inferior cul-de­sac under "open-eye" conditions. For both "spray" con­ditions, the subject's head was maintained in an upright position, and the spray atomizer was held approxi­mately 10 cm from the subject's eyes. A few moments after the cycloplegic combination was administered to the closed eyes under either drop or spray conditions, the subject was instructed to blink several times. Excess drug on the skin surfaces of the eyelids or adnexa was blotted dry. Immediately following drug instillation, the subject was asked to respond to questions about discom­fort, burning, and stinging. Tearing and avoidance of drug instillation were objectively noted by the investi­gator. These five parameters were recorded using a magnitude estimation scale from "0" to "3," with 3 being the most severe response.

Cycloplegic response was assessed by measuring residual accommodation under two conditions. In sub­jects who could reliably respond subjectively, amplitude of accommodation was measured by instructing the subject to read 0.5 M optotypes while they were moved along a Prince rule from 40 em toward the subject to the point at which the optotypes were perceived as the first sustained blur. This procedure was perfo rmed by occluding the eye not tested. Each measurement was repeated two times through the subject's best refractive correction or, if uncorrected, amplitude of accommo­dation was calculated using the subject's refractive er­ror. Amplitude of accommodation also was assessed monocularly in aU subjects using an objective retino­scope technique in which the subject was instructed to fizate various size optotypes at the plane of the reti­noscope as the examiner continually decreased the re­tinoscopic distance starting at approximately 40 cm. The point was noted at which a rapid change from

618 Journal of the American Optometric Association

0----0 pushup (drops, open) 20 ........... pushup Idrops, closed)

b---6 pushup spray, open)

e: ............... pushup (spray, closed)

z 15

\ ~ < 0 0 10 ~ ~

I I 0

" " 5 , """ <

0 ,

o 15 30 45 60

TIME (min)

Figure I : Amplitude o( accommodation wing pUlbup proce­dure ror the (our methoda o( drug delivery. Data points rep­retlent mean. ::tS.E.

20

e: z 15 0 ~ < 0 0 ~

10

~ 0

" " 5 <

0 0 15

0----0 rei (drops, open) ........... rei !drops, closed) b---6 rei spray, open) ............... ret (spray, closed)

30 45

TIME (min)

60

Figure 2: Amplitude o( accommodation using ret inollCOPY procedure (or tbe four metbods o( drug delivery. Data points represents mean. ::tS.E.

"neutrality" to "with" motion occurred, and that dis­tance (cm) was converted to amplitude of accommoda­tion using the following formula: AMP=RC-RL+RE, where AMP=amplitude of accommodation (D), RC=retinoscopic reflex change (D), RL=retinoscopy lens (D), RE=refractive error (+)hyperopia or (-)myopiaj

Following baseline examinations and drug admin­istration, subsequent measurements of amplitude of accommodation were taken at times 10, 20, 30, 45, and 60 mins.

Results

Figures 1 and 2 show the change in residual amplitude of accommodation using the two measurement tech­niques for the four methods of drug delivery. Repeated measures analysis of covariance (ANCOVA), correcting for differences in accommodation at time zero, revealed no statistically sign ificant difference in amplitude of

20 0---0 pushup (aU conditions) ___ retinoscopy (aU conditions)

. ~~~~===c==~ • 15 ~ ~ ~

TIME (min)

Figure 3: Comparieoo of pldhup and retinoeeopic metbods to aueu ampUtude of accommodation, with tbe (our drug.deUv­ery conditiOILI combined. Data poio ... npreMot me ..... ±S.E.

20

15 3.

0--0 blue Irides __ non-bll.l8 irides

45 ~

TIME (min)

Figure 4: Amplitude of aeeommodatioll io blue VI. DoD-blue eyes. nata polo ... r eprftellt meUI ±S.E. of pushup and reti­ooecopic procedurN combioed.

accommodation among the four methods of drug ad­ministration for either of the two amplitude measures [Pushup (PU), F-O.971; df-3, 26; p-0.422; Retinos­copy (RE), F-O.619, df-3, 32; p-O.608J.

To evaluate the relative ability of the pushup and retinoscopic methods to assess amplitude of accommo­dation, the slopes of the curves for each method were compared (Fig. 3). This analysis showed each method to be similar in its ability to assess amplitude of accom­modation (p>o.05).

An ANCOVA revealed no statistically significant difference in cycloplegic response for either amplitude measure based on eye color (i.e., blue vs. non-blue) (Fig. 4) [PU, F-1.837; df-I, 28; p-O.I86; RK F-1.405; df-I, 34; p=O.244j . For each eye color t here was no statisti­caUy significant difference in cycloplegic response be­tween drops and spray (Fig. 5). IPUjBlue eyes: F=O.OI4; df=I , 4; p=O.912; PU/ non-blue eyes: F=L691, df=I, 21; p-O.208; RE/Blue eye" F-O.636; df-I, 5; p-0.461; REI non-blue eyes: F=1.662; df=l. 26; p=O.209).

2Or--~~~=n e: ~ 1

O~ I. '" ~

b---..tJ. non-blue .---.... non-blue Irides

U5~~~~ ~

• • 15 ~ ~ ~

TIME (min)

Figure G: Amplitude ot accommodation in blue va. non-blue eyes under "drop" aDd ".pray" coDditioDS. nata points repre­II8Dt meaDa :2:8.E.

20

15

0--0 retinoscopy (c 8 years) __ retinoscopy (:I! 8 years) b---..tJ. pushup (c 8 years) .A.--oI. pushup (:I! 8 yeats)

30 45 60 TIME (min)

Figure 6: Amplitude of accommodation based on age, with the tour drug delivery condition. combined. Data pointe rep­r Hent mean. :t8.E.

We also found no statistically significant difference in cycloplegic response based on age (<8 years versus ,.8 yea",) (Fig. 6) [PU, F-O.182; df-I, 28; p-O.673; RE, F=1.807; df=l. 34; p=O.l88j. Within each age range there was no difference in cycloplegic response between drops and spray [PU<8: F=O.551; df=l, 8; p=0.479; PU,.8, F-3.086, df-I, 17; p-O.097; RE/<8, F-0.486; df-I,14; p-O.497; PU/,,8, F-1.l64; df-I, 17; p-O.296J.

The subjective and objective responses to the four drug administration methods have been reported else­where.'

Discussion

Topically applied sprays represent an alternative method of administering ophthalmic solutions. Sprays can be less irritating and less objectionable when com­pared with solutions given in conventional eyedrops. Various antiglaucoma medications were once commer­cially prepared in mist-dispensing bottles, but these are

Volume 64, Number 9, 9/93 819

no longer available. Combinations of mydriatics and cycloplegics have been used as sprays for routine my­driasis or cycloplegia in adults and children.1.2 The spray can be produced by using a refillable perfume atomizer that has first been asepticized by ethylene oxide gas or hydrogen peroxide before filling with the appropriate mydriatic or cycloplegic combination. The unit is held 5- 10 cm from the eye before activating the spray. The volume of a single spray emanating from our system (105 ~I) was greater than the volume of a drop obtained from a standard eyedropper.~

High uncorrected refractive errors during the neo­natal period or early childhood years may increase the risk of amblyopia or strabismus.s It is therefore impor­tant for refractive examinations of children to be per­formed carefully, and it is generally recognized that refractive examinations performed under cycloplegia yield the most reliable and valid results.6 An important disadvantage of cycloplegic refraction, however, is that the pediatric patient often experiences discomfort upon instillation of the eyedrops, which may result in alien­ating the child and reducing subsequent cooperation during the examination. Traditionally, cycloplegic re­fraction in the pediatric age group has been accom­plished by using solutions of tropicamide, cyclopento­late, and phenylephrine, instilled separately.s This com­bination of agents produces adequate mydriasis for fundus evaluation and allows effective cycloplegia for retinoscopy or subjective refraction.6

•7 Caputo and

Lingua! have recommended a combination mydriatic­cycloplegic solution that minimizes ocular irritation and provides acceptable mydriasis and cycloplegia with a single-encounter medication. We used a solution pre­pared by combining 3.75 ml cyclopentolate 2.0% with 7.5 ml tropicamide 1.0% and 3.75 ml phenylephrine 10.0%. The final, mixed solution contains cyclopento­late 0.5%, tropicamide 0.5%, and phenylephrine 2.5%. No major side effects have been reported from use of this combination mydriatic-cycloplegic solution.!

The results of our study revealed no statistically significant difference in cycloplegic response for the four methods of drug administration. It is interesting to note, however, that the maximum effect was achieved by 20-30 minutes for each of the methods. This is of practical significance since it implies that clinicians need not wait 30-45 mins following cycloplegic instil­lation before the refractive procedures begin, as is the traditional recommendation.s Although this finding is in contrast to that reported by several previous inves­tigators,9.IG Manny and associatesll have recently ob­tained similar results using cyclopentolate in the pedi­atric age group.

We have reported2 that adverse drug instillation responses among these four methods of drug delivery are not significantly different. There is less burning sensation and less avoidance reaction on the part of the

620 Journal of the American Optometric Association

child, however, when the cycloplegic solution is applied using the spray under closed-eye conditions. This would strongly suggest, therefore, that application of a cyclo­plegic spray to closed eyes is as efficacious yet more tolerable compared to the other methods of drug ad­ministration.

It is of interest that the two methods of measuring amplitude of accommodation revealed significantly dif­ferent results. The pushup method appears to demon­strate about 50 residual accommodation, whereas the retinoscopic method revealed little or no residual ac­commodation. This may be due to greater interpretive variability on the part of the child, differences in blur interpretation, or difficulty in understanding the pushup test. The greater variability inherent in the pushup method suggests that retinoscopy should be employed as the procedure of choice to ascertain resid­ual accommodation prior to cycloplegic retinoscopy or subjective refraction in children.

Due to its ease and rapidity of administration, use of a cycloplegic spray appears to be a viable alternative to conventional eyedrops for routine cycloplegic refrac­tion in the pediatric population. The results of our study suggest, moreover, that the spray can be applied to the closed eyelids, which improves tolerability and acceptance by the pediatric patient. •

References 1. Sharp J, Hanna C. Use of a spray to deliver drup to the eye. J

Arkansas Med Soc 1977; 73:462-3. 2. Wesson Mo, Bartlett JD, Swiatocha J, et aJ. Mydriatic efficacy

of a cycloplegic spray in the pediatric population. J Am Optom Auoc 1993; 64:637-40.

3. Caputo Aft, Schnitzer HE, Lindquiet TO, et al. Dilation in neonatee: a protocol. Pediatrics 1982; 69:77- 9.

4. Fraunfelder FT. Enraocule.r fluid dynamice: how beat to apply topical ocular medication •. Tran. Am Ophthahnol Soc 1976; 74:457-87.

5. Atkinson J. Braddiclr. O. Infant precurson of later visual disor­den: col'l'ei8tion or causality? In: Yong A, eel. Tbe Minnesota sympoaia on cbild PIIycbology, 1988; 20:35-65.

6. Amoa OM. Cycloplegic refraction. In: Bartlett Jo, Jaanus SO, eda. Clinical ocular pbarmacolOC)'. Boston: Butterwortb Publish­en, 1989:421-9.

7. Adame AJ, Mutti 00, ZadnilF: K, et aI. The effect of tropic amide venua cyclopentolate cycloplegia on the megurement of refrac­tive error and crylltalline lena power and tbickness. Invest Ophthalmol Via Sci 1992: 33(euppl): 709.

8. Caputo AR, Lingua ftW. The problem of cycloplegia in the pediatric age group: a combination formula for refraction. J Pediatr Ophthalmol Strabismu8 1980; 17:119-28.

9. Priestly BS, Medine MM. A new mydriatic and cycloplegic drog. Am J Opbthalmol1951; 34:572-5.

10. Gettes Bo, Leopold IH. Evaluation of five new cycloplegic drugs. Arch Opbtbalmol1953; 49:24-7.

II. Manny HE, Zervas HJ, Scott SK, et al. Objective asSI&8ment of residual accommodation follOWing in8tillation of 1% cyc.lopento­late hydrochloride. Optom Vi, Sci 1991; 68(8uppl):121.

Acknowledl me nts Tbi. work W8I supported in part by NEt Core Grant EY-03039, Clinical Vision Researcb Development Module, and by Biomedical Research Support Grant S07-RR05807, Division of Research Re-

sources, National Institutes of Health. The authors have no proprietary interest in any devices or drugs men· tioned herein. Portions of this research were presented at the annual meetings of the Association for Research in Vision and Ophthalmology, Sarasota, Florida, May 3-8, 1992, and the American Academy of Optometry. Orlando, Florida, December 10-14, 1992. DennisJ. Phil· lips, Ph.D., assisted in determining the spray volume.

Submitted 2/93; accepted 3/93

Jimmy D. Bartlett, O. D. University of Alabama at Birmingham

School of Optometry 1716 University Blvd.

Birmingham, AL 35294

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